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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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IPRAGLIFLOZIN, NEW PATENT, WO2016173551, China State Institute of Pharmaceutical Industry; Shanghai Institute of Pharmaceutical Industry


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WO 2016173551 China State Institute of Pharmaceutical Industry; Shanghai Institute of Pharmaceutical Industry

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016173551&redirectedID=true

MA, Shuai; (CN).
ZHOU, Weicheng; (CN)

WO2016173551,  IPRAGLIFLOZIN PREPARATION METHOD

CHINA STATE INSTITUTE OF PHARMACEUTICAL INDUSTRY [CN/CN]; 4th Floor, Building 1, No.1111 Halley Road,pudong New Area Shanghai 201203 (CN).
SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY [CN/CN]; No.1320,West Beijing Road,Jing’an District Shanghai 200040 (CN)

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MACHINE TRANSLATED FROM CHINESE……

Ignatius column Net (English name: Ipragliflozin) by Astellas Pharma Ltd. (Astellas) new sodium life Pharmaceutical Co., Ltd. (Kotobuki) R & D – glucose cotransporter (Sodium glucose co-transporters, referred to as SGLT-2 ) inhibitor, on January 17, 2014 in the Japanese market for the treatment of patients with type ⅱ diabetes; tradename Suglat, currently provide 25mg and 50mg tablets.

 

Chemical Name column Ignatius net is (1S) -1,5- dehydration -1-C- [3- (1- benzothien-2-yl-methyl) -4-fluorophenyl] -D-glucose alcohols of the formula the C 21 the H 21 the FO 5 the S, the CAS No. 761423-87-4, as the structure of formula 2, as a column for medicinal Eagle with L- proline net clinical eutectics, such as a structural formula FIG.

 

 

Ignatius column in the process of preparation of the net, the chiral synthesis of β glycoside bond synthetic route key points. Currently, Ignatius column net of synthetic methods reported in the literature there are several of these methods for the synthesis of chiral β-glucoside bonds mainly relates to hydroxy-protected D- glucose lactone ester carbonyl nucleophilic addition reaction.

 

Route One: Patent WO2004080990 synthetic route reported net Ignatius column is as follows:

 

This route, [1-benzopyran-2-yl (5-bromo-2-fluorophenyl) methoxy] (tert-butyl) dimethylsilane (Compound 10) with n-butyl lithium at -78 deg.] C (or minus 78 deg.] C) the reaction of an organolithium reagent and then with 2,3,4,6-tetra -O- benzyl -D- glucose lactone (compound 9) nucleophilic addition at low temperature -78 ℃ to obtain compound 8, followed by removal of the silicon compound 8 hydroxy group is protected with tetrabutylammonium fluoride (of TBAF) to give compound 7, triethylsilane and then reducing the compound 7 obtained with chiral β glycosidic bond Ignatius column net intermediate 6, the last off at -78 ℃ intermediate ring 6 sugar hydroxyl protecting groups to obtain the desired product – Ignatius column net (compound 2). Compound 10 was prepared by the target product – Ignatius column net synthesis route yield 9.94%, net Ignatius column purity not reported. The disadvantage of this method is that a long synthetic route, after every step of the reaction were purified by column chromatography, and the yield is low. Deprotecting the hydroxy group on two key steps chiral β glycosidic bond synthesis and sugar ring need to be at a low temperature at -78 deg.] C, clearly, it is difficult to meet the needs of industrial production.
Route II: Patent WO2008075736 Ignatius column reported net synthetic route is as follows:

 

 

The route of 2- (5-bromo-2-fluorobenzyl) benzothiophene (compound 15) with n-butyl lithium at -43.5 ~ -33.3 ℃ reaction of an organolithium reagent and then with 2,3,4 , 6-tetrafluoro -O- trimethylsilyl -D- glucose lactone (compound 14) nucleophilic addition reactions at -72.6 ~ -65 ℃ to give compound 13, compound 13 and then acetylation, reduction Ignatius column net intermediates prepared with chiral β glycoside bond of 11, finally deacetylated to obtain the desired product of intermediate 11 – Ignatius column net (compound 2). Compound 15 was prepared by the Scheme 2 the desired product in a yield of 72.46%, a purity of compound 2 was 99%. The disadvantage of this method is that the route Ignatius column net synthesis requires at a low temperature of -72.6 ℃ to react and involve nucleophilic addition reaction, a hydroxyl group on the terminal carbon methylation, acetylation of hydroxyl groups on the sugar ring, the end methoxy groups on carbon reduction, the reaction and post-treatment process is very complicated, more difficult to industrial production, and on the terminal carbon-methoxy-reducing agent used in the reduction – t-butyldimethylsilyl more expensive, increasing the whole synthetic route costs.

 

Route III: Patent WO2015012110 Ignatius column reported net synthetic route is as follows:

 

On the basis of patent WO2015012110 patent WO2008075736 reported synthetic route for the synthesis net Ignatius column primarily relates to the further improvements: namely: 2- (5-bromo-2-fluorobenzyl) benzothiophene (Compound 15) three butylmagnesium lithium at -12 ~ -26 ℃ organomagnesium reagent prepared by the reaction – compound 16, and then with 2,3,4,6-tetra -O- trimethylsilyl -D- glucose lactone (compound 14) carried out at -12 ~ -16 ℃ nucleophilic addition reaction Ignatius column net key intermediates – compounds 13, this step is nucleophilic addition reaction temperature was raised to -26 ℃, avoid the use of other organic lithium reagent required -78 ℃ low temperature reactions. The disadvantage of this method is that Ignatius column net synthesis still need to involve nucleophilic addition reaction, a hydroxyl group on the terminal carbon methylation, acetylation of hydroxyl groups on the sugar ring, a methoxy group on the terminal carbon reduction reaction and post-treatment very complicated problem is not resolved; in addition, tributyltin lithium magnesium used in the route in the country not commercially available, and can be prepared before the experiment, the manufacturing process is more complex, more difficult to industrial production.

 

Skilled in the art knows the energy super low temperature chemical reaction operations is considerable. Generally, the reaction temperature at -40 ℃ over the operation of the more conventional reactor in the plant can be relatively easy to do; but lower than the reaction below -40 ℃ the need to use special equipment or a special reactor is required with liquid nitrogen as the cooling source, the higher the cost. For ultra-low temperature improvements often become enlarged or when the process of large-scale, process optimization of key points.

 

In the background art described in this article about the Ignatius column net three synthetic route, the “connection” between the main synthon mainly related to the organometallic reagents – such as organic lithium or magnesium organic lithium reagents protected hydroxy D- glucose ester carbonyl lactone on nucleophilic substitution reaction with hydroxyl groups to form the corresponding glucose derivative on the terminal carbon; then after hydroxy or derivatives thereof – methoxy reduced to hydrogen, to give the title with β-type hand glycoside bond Ignatius column net key intermediate structure; and finally the removal of hydroxy protecting groups on the pyranose ring to give Ignatius column net. In these types of synthetic route, operation and post-processing reaction steps are more complicated, the cost is high. For example, in Scheme 1 and 2, both the use of ultra-low temperature organolithium reagent – minus 78 ℃; several synthetic route in addition, most of the intermediate purification using column chromatography, such process is not suitable for plant production is amplified. Therefore, an urgent need to find new Ignatius column net synthesis method, and enables industrial production.

 

(1), from 4-fluoro-3- (2-benzothienyl) phenyl methyl halide (Compound 5) as a starting material, the compound 5 in a suitable solvent, is reacted with an alkyl lithium, followed by reaction with zinc an organic zinc reagent – bis [4-fluoro-3- (2-benzothienyl) methyl phenyl] zinc, and then with 2,3,4,6-tetra -O- pivaloyl bromo -α-D- Generation glucopyranose (compound 4) nucleophilic substitution reaction of intermediate net Ignatius column – compound 3;
(2), compound 3 by an organic base off pivaloyl protecting group to obtain Eagle column net (Compound 2);

 

Wherein in the 4-fluoro-3- (2-benzothienyl) phenyl methyl halide (Compound 5) Structure X is selected from bromo or iodo;

 

Synthetic route is as follows:

 

 

Example 1, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Preparation fluorophenyl] glucitol (compound 3) –
Zinc bromide (0.676 g) and lithium bromide (0.261 g) was added n-butyl ether (8mL), stirred and heated to 50 deg.] C 2h, cooling backup. Under nitrogen, was added 2- (5-iodo-2-fluorobenzyl) benzothiophene (2.21g) in toluene (5mL), n-butyl ether (5mL), cooled to -25 deg.] C, was slowly added dropwise 1.6mol / L n-hexyl lithium hexane solution (4.13 ml), to control the internal temperature does not exceed -10 deg.] C, after the addition was complete the reaction was incubated at -20 ℃ 0.5h, a solution of n-butyl ether was added to the backup lithium bromide and zinc bromide, at 10 ℃ reaction was stirred 3h. Was added 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (3.48 g of) in toluene (10 mL) solution and heated to 80 deg.] C the reaction was stirred 6h, TLC analysis after completion of the reaction, was added 1mol / L dilute hydrochloric acid (7mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, concentrated, and n-heptane (5mL) and methanol (15mL) recrystallized 3.452g 3 of solid compound, yield: 77.65%. Purity: 99.45%. Melting point: 128.9 ~ 130.5 ℃. 1 the H-NMR (CDCl 3 ): [delta] 7.72 (IH, D), 7.64 (IH, D), 7.21-7.30 (4H, m), 7.04 (IH, T), 6.96 (IH, S), 5.40 ( 1H, t), 5.27 (2H , m), 4.36 (1H, d), 4.08-4.21 (4H, m), 3.82 (1H, dd), 1.19 (9H, s), 1.16 (9H, s), 1.11 (9H, s), 0.85 ( 9H, s).
Example 2, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Preparation fluorophenyl] glucitol (compound 3) –
Zinc bromide (0.676 g) and lithium bromide (0.261 g) was added n-butyl ether (8mL), stirred and heated to 50 deg.] C 2h, cooling backup. Under nitrogen, was added 2- toluene (5mL) (5- iodo-2-fluorobenzyl) benzothiophene (2.21g) in n-butyl ether (5mL), cooled to – 50 ℃, was slowly added dropwise 2.5mol / L n-butyllithium hexane solution (2.64 mL), controlling the internal temperature does not exceed -30 deg.] C, 6h after the addition was complete the reaction was kept at -50 deg.] C, was added a solution of n-butyl ether in said auxiliary zinc bromide and lithium bromide, the reaction was stirred 8h at -20 ℃. Was added 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (6.954g) in toluene (12mL) solution, heated to 25 deg.] C the reaction was stirred 24h, after completion of the reaction by TLC, was added 1mol / L dilute hydrochloric acid (8mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, concentrated, and n-heptane (5mL) and methanol (15mL) recrystallized 3.237g 3 of solid compound, yield: 72.81%. Purity: 99.36%.
Example 3, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Preparation fluorophenyl] glucitol (compound 3) –
Zinc iodide (1.915g) and lithium iodide (0.803 g) in n-butyl ether was added (10mL), stirred and heated to 50 deg.] C 1.5h, cool reserve. Under nitrogen, was added 2- (5-iodo-2-fluorobenzyl) benzothiophene (2.21g) in toluene (9mL), n-butyl ether (3mL), cooled to -30 deg.] C, was slowly added dropwise 1.6mol / L n-hexyl lithium hexane solution (4.13mL), controlling the internal temperature does not exceed -20 ℃, n-butyl ether solution after the addition was complete the reaction was kept at -30 ℃ at 5h, zinc iodide was added to the backup and lithium iodide the mixture was stirred at 25 ℃ reaction 1h. After addition of 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (4.346g) in toluene (10 mL) solution, the reaction was heated to reflux for 145 ℃ 0.5h, TLC detection completion of the reaction , was added 1mol / L dilute hydrochloric acid (8mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, concentrated, and n-heptane (5mL) and methanol (15mL) recrystallized 3.552 3 g of a solid compound in a yield of 79.9%. Purity: 99.41%.
Example 4, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Preparation fluorophenyl] glucitol (compound 3) –
Zinc bromide (0.676 g) and lithium bromide (0.261 g) was added n-butyl ether (7mL), stirred and heated to 50 deg.] C 2h, cooling backup. Under nitrogen atmosphere, 2- (5-bromo-2-yl) benzothiophene (1.927g) was added toluene (6mL), n-butyl ether (4mL), cooled to -30 deg.] C, was slowly added dropwise 2.5mol / L n-butyllithium hexane solution (2.88 mL), controlling the internal temperature does not exceed -20 deg.] C, 3h after the addition was complete the reaction was kept at -30 deg.] C, was added a solution of n-butyl ether in said auxiliary zinc bromide and lithium bromide, the reaction was kept at -5 ℃ 4h, was added 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (4.346g) in toluene (7mL) solution, stirred and heated to 120 ℃ The reaction 4h, after completion of the reaction by TLC, was added 1mol / L dilute hydrochloric acid (8mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, and concentrated under reduced pressure, n-heptane (5mL ) and methanol (15mL) recrystallized 2.783g solid compound 3, yield: 62.6%. Purity: 99.29%.
EXAMPLE 5, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Preparation fluorophenyl] glucitol (compound 3) –
Zinc bromide (0.676 g) and lithium bromide (0.261 g) was added cyclopentyl ether (8mL), stirred and heated to 50 deg.] C 2h, cooling backup. Under nitrogen, was added 2- (5-iodo-2-fluorobenzyl) benzothiophene (2.21g) in toluene (6mL), cyclopentyl methyl ether (6mL), cooled to -30 deg.] C, was slowly added dropwise 1.6 mol / L hexane solution of n-hexyl lithium (4.5mL), controlling the internal temperature does not exceed -20 ℃, after the addition was complete the reaction was kept at -30 ℃ at 3h, added to the backup lithium bromide and zinc bromide cyclopentylmethyl the ether solution, the reaction incubated at -5 ℃ 4h, was added 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (4.346g) in toluene (8mL) solution, heated to 120 ℃ reaction was stirred 4h, after completion of the reaction by TLC, was added 1mol / L dilute hydrochloric acid (8mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, and concentrated under reduced pressure, with n-heptane dioxane (5mL) and methanol (15mL) recrystallized 2.088g solid compound 3, yield: 47%. Purity: 99.3%.
6, (1S) -2,3,4,6- four -O- pivaloyl anhydro-1- [3- (1-thiophen-2-yl-methyl) -4 Example Preparation fluorophenyl] glucitol (compound 3) –
Zinc bromide (0.676 g) and lithium bromide (0.261 g) was added methyl t-butyl ether (8mL), was heated to 50 ℃ stirred 3h, cooling backup. Under nitrogen, was added 2- toluene (6mL), methyl t-butyl ether (4mL) (5- iodo-2-fluorobenzyl) benzothiophene (2.21g), cooled to -40 deg.] C, was slowly added dropwise 1.6 mol / L n-hexyl lithium hexane solution (3.94mL), controlling the internal temperature does not exceed -30 ℃, after the addition was complete the reaction was kept at -40 ℃ at 4h, was added to the lithium bromide and zinc bromide spare methyl tert-butyl ether solution, the reaction incubated at 5 ℃ 7H, was added 2,3,4,6-tetra -O- pivaloyl bromo -α-D- glucopyranose (3.48 g of) in toluene (8mL) solution, heated to 90 ℃ reaction was stirred 6h, after completion of the reaction by TLC, was added 1mol / L dilute hydrochloric acid (8mL), water (20 mL), the combined organic phase was washed with water, dried over anhydrous of Na 2 the SO 4 dried, and concentrated under reduced pressure, with n-heptane dioxane (5mL) and methanol (15mL) recrystallized 2.792g solid compound 3, yield: 62.8%. Purity: 99.44%.
Example 7, (1S) -1,5- anhydro-1- [3- (1-methyl-thiophen-2-yl) -4-fluorophenyl] -D-glucitol (Compound 2) preparation
Compound 3 (7.41g) was added methanol (35mL), was added sodium methoxide (2.161g), heated at reflux for 5H reaction, after completion of the reaction by TLC, concentrated and the residue was added methanol (10 mL), water (10 mL), acetic acid ( 3g), was added seed crystal (0.1g), stirred at 5 ℃ crystallization, filtration, the filter cake washed with cold (methanol: (5mL) was washed with 1) solvent to give an off-white solid 3.89g compound 2: water = 1 , yield: 96.2%. Purity: 99.29%. 1 the H-NMR (the CD 3 the OD): [delta] 7.70 (IH, D), 7.63 (IH, D), 7.43 (IH, dd), 7.34-7.38 (IH, m), 7.21-7.26 (2H, m) , 7.08 (1H, t), 7.01 (1H, s), 4.18-4.28 (2H, m), 4.12 (1H, d), 3.88 (1H, dd), 3.70 (1H, dd), 3.30-3.50 (4H , m).
Example 8, (1S) -1,5- anhydro-1- [3- (1-methyl-thiophen-2-yl) -4-fluorophenyl] -D-glucitol (Compound 2) preparatio
Methanol was added (15mL) of the compound 3 (7.41g) was added sodium hydroxide (2g) in water (10 mL) solution was heated to 50 deg.] C the reaction was stirred 10h, TLC detection after completion of the reaction, water (10mL), 2mol / L hydrochloric acid (2mL), stirred at room temperature for crystallization, white solid was suction filtered, the filter cake washed with water (5mL) was washed and dried to give 3.806g of compound 2, yield: 94.1%. Purity: 99.31%.
Preparation 9, Ignatius column eutectic net L- proline (Compound 1) Example
Net Ignatius column (compound 2) (4.04g) was added ethanol (25mL), was added L- proline (1.15 g of), the reaction was heated at reflux for 1h, cooled to room temperature, filtered, the filter cake washed with cold ethanol, and dried to give white solid 4.67g of compound 1. Yield: 90%. Purity: 99.51%. Melting point: 194.0 ~ 202.1 ℃. The MS-ESI (m / Z): 427.16 [the M + of Na] + . 1 the H-NMR (the CD 3 the OD): [delta] 7.75 (IH, D), 7.67 (IH, D), 7.45 (IH, dd), 7.37 (IH, m), 7.24-7.31 (2H, m), 7.10 (1H, t), 7.07 ( 1H, s), 4.23-4.32 (2H, m), 4.13 (1H, d), 3.98 (1H, t), 3.89 (1H, d), 3.71 (1H, dd),3.31-3.50 (5H, m), 3.21-3.27 (1H, m), 2.27-2.34 (1H, m), 2.09-2.17 (1H, m), 1.95-2.02 (2H, m).

Claims

Ignatius one kind of column and net synthesis process, comprising the steps of: (1), from 4-fluoro-3- (2-benzothienyl) methyl-5-phenyl-halide as a raw material, in an appropriate solvent 5 is reacted with an alkyl lithium, followed by reaction with the zinc salt prepared organozinc reagents – bis [4-fluoro-3- (2-benzothienyl) methyl phenyl] zinc, and then with 2,3,4,6-tetra -O- pivaloyl -α-D- glucopyranose 4-bromo nucleophilic substitution reaction of intermediate net Ignatius column 3; (2), compound 3 by an organic base off pivaloyl protecting group prepared net Ignatius column 2; wherein, in the 4-fluoro-3- (2-benzothienyl) methyl-5-phenyl halide of structure X is selected from bromo or iodo; synthesis route is as follows:

////////WO 2016173551, China State Institute of Pharmaceutical Industry; Shanghai Institute of Pharmaceutical Industry, IPRAGLIFLOZIN, NEW PATENT,

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ANTHONYFLOZIN………Find one if you can in this review


find here

http://medcheminternational.blogspot.in/p/flozin-series.html

1 TOFOGLIFLOZIN
2 SERGLIFLOZIN
3 DAPAGLIFLOZIN
4 IPRAGLIFLOZIN
5 EMPAGLIFLOZIN
6 LUSEOGLIFLOZIN
7 REMOGLIFLOZIN
8 ERTUGLIFLOZIN
9 SOTAGLIFLOZON

DR ANTHONY

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Ipragliflozin


Ipragliflozin

ASP-1941 ,   1(S)-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-1-deoxy-beta-D-glucopyranose L-proline cocrystal

Kotobuki (Originator)

(1S)-1,5-Anhydro-1-C-[3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl]-D-glucitol
Molecular Formula C21H21FO5S
Molecular Weight 404.45
CAS Registry Number 761423-87-4

Ipragliflozin (formerly ASP1941) has been filed in Japan on the back of phase III trials which showed that it could provide significant reductions in glycated haemoglobin levels (HbA1c) levels – a marker of glucose control over time – compared to placebo

According to Astellas’ latest R&D pipeline update in February 2013, Astellas is developing ipragliflozin only in Japan. The same document in August 2012 indicated it was also carrying out phase II studies with the drug in the US and Japan.

Astellas Pharma Inc.: Submits Application for Marketing Approval of
Ipragliflozin (ASP1941), SGLT2 Inhibitor for Treatment of
Type 2 Diabetes, in Japan
TOKYO, March 13, 2013 – Astellas Pharma Inc. (“Astellas”; Tokyo:4503; President and CEO:
Yoshihiko Hatanaka) announced today that it has submitted a market authorization application for aSGLT2 inhibitoripragliflozin (generic name; development code: ASP1941) to the Ministry of Health, Labour and Welfare in Japan seeking an approval forthe indication of type 2 diabetes.
Ipragliflozin is a selective SGLT2 (sodium-glucose co-transporter 2)inhibitor discovered through research collaboration with Kotobuki Pharmaceutical Co., Ltd. SGLTs are membrane proteins that
exist on the cell surface and transfer glucose into cells. SGLT2 is a subtype of the sodium-glucose co-transporters and plays a key role in the reuptake of glucose in the proximal tubule of the kidneys.
Ipragliflozin reduces blood glucose levels by inhibiting the reuptake of glucose.
In the Phase III pivotal study in monotherapy for type 2 diabetesin Japan, ipragliflozin
demonstrated significant decreases of HbA1c, an index of glycemic control, in change from baseline compared to placebo. Based on the safety resultsin this study, ipragliflozin was safe and well tolerated. Patients with type 2 diabetes generally need combination therapy, so it is important
for a novel oral hypoglycemic agent to be safe to use with existing diabetes therapies. In this regard, Astellas has conducted six Phase III studies to investigate the safety and efficacy of ipragliflozin
used in combination with other hypoglycemic agentsfor a long term period. In these Phase IIIstudies, effectiveness and favorable safety of ipragliflozin was confirmed even in combination with
other hypoglycemic agents.
Astellas expects to provide an additional therapeutic option and further contribute to the treatment of type 2 diabetes by introducing ipragliflozin, an oral hypoglycemic agent with a novel mechanism
of action, into the Japanese market.
About Type 2 Diabetes
Diabetes (medically known as diabetes mellitus) is a disorder in which the body has difficulty regulating its blood glucose (sugar) level. There are two major types of diabetes: type 1 and type 2.
Type 2 diabetes (formerly called non-insulin-dependent diabetes mellitus or adult-onset diabetes) is a disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Patients are instructed to increase exercise and diet restrictions, but most
require treatment with an anti-diabetic agent to control blood glucose.

structure:

Figure US20130035281A1-20130207-C00015

The compound and methods of its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475 for example.

The gluconolactone method: In 1988 and 1989 a general method was reported to prepare C-arylglucosides from tetra-6>-benzyl protected gluconolactone, which is an oxidized derivative of glucose (see J. Org. Chem. 1988, 53, 752-753 and J. Org. Chem. 1989, 54, 610- 612). The method comprises: 1) addition of an aryllithium derivative to the hydroxy-protected gluconolactone to form a hemiketal (a.k.ci., a lactol), and 2) reduction of the resultant hemiketal with triethylsilane in the presence of boron trifluoride etherate. Disadvantages of this classical, but very commonly applied method for β-C-arylglucoside synthesis include:

1) poor “redox economy” (see J. Am. Chem. Soc. 2008, 130, 17938-17954 and Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN- 10: 0120594757); pg 38)— that is, the oxidation state of the carbon atom at CI, with respect to glucose, is oxidized in the gluconolactone and then following the arylation step is reduced to provide the requisite oxidation state of the final product. 2) due to a lack of stereospecificity, the desired β-C-arylglucoside is formed along with the undesired a-C-arylglucoside stereoisomer (this has been partially addressed by the use of hindered trialkylsilane reducing agents (see Tetrahedron: Asymmetry 2003, 14, 3243-3247) or by conversion of the hemiketal to a methyl ketal prior to reduction (see J. Org. Chem. 2007, 72, 9746-9749 and U.S. Patent 7,375,213)).

Oxidation Reduction

Figure imgf000004_0001

Glucose Gluconoloctone Hemiketal a-anomer β-anomer

R = protecting group

The metalated glucal method: U.S. Patent 7,847,074 discloses preparation of SGLT2 inhibitors that involves the coupling of a hydroxy-protected glucal that is metalated at CI with an aryl halide in the presence of a transition metal catalyst. Following the coupling step, the requisite formal addition of water to the C-arylglucal double bond to provide the desired C-aryl glucoside is effected using i) hydroboration and oxidation, or ii) epoxidation and reduction, or iii) dihydroxylation and reduction. In each case, the metalated glucal method represents poor redox economy because oxidation and reduction reactions must be conducted to establish the requisite oxidation states of the individual CI and C2 carbon atoms.

U.S. Pat. Appl. 2005/0233988 discloses the utilization of a Suzuki reaction between a CI -boronic acid or boronic ester substituted hydroxy-protected glucal and an aryl halide in the presence of a palladium catalyst. The resulting 1- C-arylglucal is then formally hydrated to provide the desired 1- C-aryl glucoside skeleton by use of a reduction step followed by an oxidation step. The synthesis of the boronic acid and its subsequent Suzuki reaction, reduction and oxidation, together, comprise a relatively long synthetic approach to C-arylglucosides and exhibits poor redox economy. Moreover, the coupling catalyst comprises palladium which is toxic and therefore should be controlled to very low levels in the drug substance.

Figure imgf000004_0002

R = protecting group; R’ = H or alkyl

The glucal epoxide method: U.S. Patent 7,847,074 discloses a method that utilizes an organometallic (derived from the requisite aglycone moiety) addition to an electrophilic epoxide located at C1-C2 of a hydroxy-protected glucose ring to furnish intermediates useful for SGLT2 inhibitor synthesis. The epoxide intermediate is prepared by the oxidation of a hydroxy- protected glucal and is not particularly stable. In Tetrahedron 2002, 58, 1997-2009 it was taught that organometallic additions to a tri-6>-benzyl protected glucal-derived epoxide can provide either the a-C-arylglucoside, mixtures of the a- and β-C-arylglucoside or the β-C-arylglucoside by selection of the appropriate counterion of the carbanionic aryl nucleophile (i.e., the

organometallic reagent). For example, carbanionic aryl groups countered with copper (i.e., cuprate reagents) or zinc (i.e., organozinc reagents) ions provide the β-C-arylglucoside, magnesium ions provide the a- and β-C-arylglucosides, and aluminum (i.e., organoaluminum reagents) ions provide the a-C-arylglucoside.

Figure imgf000005_0001

or Zn

The glycosyl leaving group substitution method: U.S. Patent 7,847,074, also disclosed a method comprising the substitution of a leaving group located at CI of a hydroxy-protected glucosyl species, such as a glycosyl halide, with a metalated aryl compound to prepare SGLT2 inhibitors. U.S. Pat. Appl. 2011/0087017 disclosed a similar method to prepare the SGLT2 inhibitor canagliflozin and preferably diarylzinc complexes are used as nucleophiles along with tetra- >-pivaloyl protected glucosylbromide.

Figure imgf000005_0002

Glucose Glucosyl bromide β-anomer

Methodology for alkynylation of 1,6-anhydroglycosides reported in Helv. Chim. Acta. 1995, 78, 242-264 describes the preparation of l,4-dideoxy-l,4-diethynyl^-D-glucopyranoses (a. La., glucopyranosyl acetylenes), that are useful for preparing but-l,3-diyne-l,4-diyl linked polysaccharides, by the ethynylating opening (alkynylation) of partially protected 4-deoxy-4-C- ethynyl-l,6-anhydroglucopyranoses. The synthesis of β-C-arylglucosides, such as could be useful as precursors for SLGT2 inhibitors, was not disclosed. The ethynylation reaction was reported to proceed with retention of configuration at the anomeric center and was rationalized (see Helv. Chim. Acta 2002, 85, 2235-2257) by the C3-hydroxyl of the 1,6- anhydroglucopyranose being deprotonated to form a C3-0-aluminium species, that coordinated with the C6-oxygen allowing delivery of the ethyne group to the β-face of the an oxycarbenium cation derivative of the glucopyranose. Three molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6-anhydroglucopyranose. The

ethynylaluminium reagent was prepared by the reaction of equimolar (i.e., 1:1) amounts of aluminum chloride and an ethynyllithium reagent that itself was formed by the reaction of an acetylene compound with butyllithium. This retentive ethynylating opening method was also applied (see Helv. Chim. Acta. 1998, 81, 2157-2189) to 2,4-di-<9-triethylsilyl- 1,6- anhydroglucopyranose to provide l-deoxy-l-C-ethynyl- -D-glucopyranose. In this example, 4 molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6- anhydroglucopyranose. The ethynylaluminium regent was prepared by the reaction of equimolar (i.e., 1: 1) amounts of aluminum chloride and an ethynyl lithium reagent that itself was formed by reaction of an acetylene compound with butyllithium.

It can be seen from the peer-reviewed and patent literature that the conventional methods that can be used to provide C-arylglucosides possess several disadvantages. These include (1) a lack of stereoselectivity during formation of the desired anomer of the C- arylglucoside, (2) poor redox economy due to oxidation and reduction reaction steps being required to change the oxidation state of CI or of CI and C2 of the carbohydrate moiety, (3) some relatively long synthetic routes, (4) the use of toxic metals such as palladium, and/or (5) atom uneconomic protection of four free hydroxyl groups. With regard to the issue of redox economy, superfluous oxidation and reduction reactions that are inherently required to allow introduction of the aryl group into the carbohydrate moiety of the previously mention synthetic methods and the subsequent synthetic steps to establish the required oxidation state, besides adding synthetic steps to the process, are particular undesirable for manufacturing processes because reductants can be difficult and dangerous to operate on large scales due to their flammability or ability to produce flammable hydrogen gas during the reaction or during workup, and because oxidants are often corrosive and require specialized handling operations (see Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN-10: 0120594757); pg 38 for discussions on this issue).

  • The C-glycoside derivative represented by the formula (1) and its salt [hereinafter, they are referred to as “compound (1)” or “compound of formula (1)” in some cases] is known to be useful for treatment and prevention of diabetes such as insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes) and the like and various diabetes-related diseases including insulin-resistant diseases and obesity (Patent Literature 1).
  • Figure imgb0001
    Figure imgb0002
  • The method for producing the C-glycoside derivative represented by the formula (1), described in the Patent Literature 1 is understood to be represented by the below-shown reaction formula (I), by referring to the Examples and Reference Examples, described in the Patent Literature 1. Roughly explaining, it is a method which comprises reacting [1-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy]tert-butyl)dimethylsilane (synthesized in accordance with Reference Example 37 of the Literature) in a manner shown in Example 65 of the Literature, to obtain (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol and then reacting the obtained compound in accordance with Example 100 of the Literature to synthesize intended (1S)-1,5-anhydro-1-C-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol.
  • Figure imgb0003
    Figure imgb0004
  • However, the method for producing the C-glycoside derivative of the formula (1), disclosed in the Patent Literature 1 is not industrially satisfactory in yield and cost, as is seen in later-shown Reference Example 1 of the present Description.
  • For example, as described later, the method includes a step of low product yield (for example, a step of about 50% or lower yield) and the overall yield of the C-glycoside derivative (final product) represented by the formula (1) from the compound (8) (starting raw material) is below 7%; therefore, the method has problems in yield and cost from the standpoint of medicine production and has not been satisfactory industrially. In addition, the method includes an operation of purification by column chromatography which uses chloroform as part of purification solvents; use of such a solvent poses a problem in environmental protection and there are various restrictions in industrial application of such an operation; thus, the method has problems in providing an effective medicine.
  • Also, an improved method of conducting an addition reaction with trimethylsilyl carbohydrate instead of benzyl carbohydrate and then conducting deprotection for acetylation, is known for a compound which has a structure different from that of the compound of the formula (1) but has a structure common to that of the compound of the formula (1) (Patent Literature 2). It is described in the Patent Literature 2 that the improved method enhances the overall yield to 6.2% from 1.4%. Even in the improved method, however, the yield is low at 6.2% which is far from satisfaction in industrial production.

Figure imgb0022

http://www.google.com/patents/EP2105442A1

      First step: synthesis of 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol

    • Into a tetrahydrofuran (20 ml) solution of benzo[b]thiophene (5.0 g) was dropwise added a n-hexane solution (25 ml) of n-butyl lithium (1.58 M) at -78°C in an argon atmosphere, followed by stirring at -78°C for 10 minutes. Into this solution was dropwise added a tetrahydrofuran (80 ml) solution of 5-bromo-2-fluorobenzaldehyde (8.0 g), followed by stirring at -78°C for 2.5 hours. The temperature of the reaction mixture was elevated to room temperature. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (10.5 g, yield: 83.6%).
      1H-NMR (CDCl3): δ
      2.74 (1H, d), 6.35 (1H, d), 6.93 (1H, dd), 7.14 (1H, s), 7.27-7.38 (2H, m), 7.39 (1H, m), 7.68 (1H, dd), 7.74 (2H, m)

Second step: synthesis of [1-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy](tert-butyl)dimethylsilane

    • To a dimethylformamide (20 ml) solution of 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (5.0 g) were added imidazole (1.3 g), a catalytic amount of 4-(dimethylamino)pyridine and tert-butyldimethylchlorosilane (2.7 g), followed by stirring at room temperature for 7 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain [1-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy](tert-butyl)dimethylsilane (5.22 g, yield: 78.0%).
      MS: 451 (M+)
      1H-NMR (CDCl3): δ
      0.05 (3H, s), 0.11 (3H, s), 0.95 (9H, s), 6.34 (1H, s), 6.91 (1H, t), 7.08 (1H, d), 7.23-7.38 (2H, m), 7.64-7.68 (1H, m), 7.75-7.28 (2H, m)

Third step: Synthesis of 1-C-[3-(1-benzothien-2-yl{[tert-butyl-(dimethyl)silyloxy}methyl)4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose

    • Into a tetrahydrofuran (15 ml) solution of [1-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy](tert-butyl)dimethylsilane (1.5 g) was dropwise added a n-hexane solution (2.2 ml) of n-butyl lithium (1.58 M) in an argon atmosphere at -78°C, followed by stirring at -78°C for 30 minutes. Into the solution was dropwise added a tetrahydrofuran (20 ml) solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (1.9 g), followed by stirring at -78°C for 15 minutes and then at 0°C for 1.5 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/chloroform/acetone) to obtain 1-C-[3-(1-benzothien-2-yl{[tert-butyl-(dimethyl)silyloxy}methyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose (1.52 g, yield: 50.2%). MS: 933 (M+Na)

Fourth step: Synthesis of 1-C-{3-[1-benzothien-2-yl(hydroxy)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-benzyl-D-glucopyranose

    • To a tetrahydrofuran (15 ml) solution of 1-C-[3-(1-benzothien-2-yl{[tert-butyl-(dimethyl)silyloxy}methyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose (1.52 g) was added a tetrahydrofuran solution (2.0 ml) of tetrabutylammonium fluoride (1.0 M), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated per se. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-C-{3-[1-benzothien-2-yl(hydroxy)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-benzyl-D-glucopyranose (0.99 g, yield: 74.7%). MS: 819 (M+Na), 779 (M+H-H2O)

Fifth step: Synthesis of (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol

    • To an acetonitrile (5.0 ml) solution of 1-C-{3-[1-benzothien-2-yl(hydroxy)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-benzyl-D-glucopyranose (500 mg) were added triethylsilane (175 mg) and boron trifluoride-diethyl ether complex (196 mg) in an argon atmosphere at -20°C, followed by stirring at -20°C for 5 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol (150 mg, yield: 30.2%) MS: 787 (M+Na)
      1H-NMR (CDCl3): δ
      3.42-3.48 (1H, m), 3.55-3.58 (1H, m), 3.72-3.78 (4H, m), 3.83 (1H, d), 4.14-4.30 (3H, m), 4.39 (1H, d), 4.51-4.67 (4H, m), 4.83-4.94 (2H, m), 6.86-6.90 (1H, m), 6.98 (1H, brs), 7.06-7.37 (24H, m), 7.57-7.60 (1H, m), 7.66-7.69 (1H, m)

Sixth step: Synthesis of (1S)-1,5-anhydro-1-C-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol

  • To a dichloromethane (10 ml) solution of (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol (137 mg) were added pentamethylbenzene (382 mg) and a n-heptane solution (0.75 ml) of boron trichloride (1.0 M) in an argon atmosphere at -78°C, followed by stirring at -78°C for 3 hours. Methanol was added to the reaction mixture, the temperature of the resulting mixture was elevated to room temperature, and the mixture was concentrated per se. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain (1S)-1,5-anhydro-1-C-[3-(1-benzothiophene-2-ylmethyl)-4-fluorohenyl]-D-glucitol  OR IPRAGLIFLOZIN (63 mg, yield: 87.8%).
    1H-NMR (CD3OD): δ
    3.29-3.48 (4H, m), 3.68 (1H, dd), 3.87 (1H, dd), 4.11 (1H, d), 4.20-4.29 (2H, m), 7.03 (1H, s), 7.08 (1H, dd), 7.19-7.29 (2H, m), 7.35 (1H, m), 7.42 (1H, dd), 7.64 (1H, d), 7.72 (1H, d)

Figure imgb0002

(1S)-1,5-anhydro-1-C-[3-(1-benzothiophene-2-ylmethyl)-4-fluorohenyl]-D-glucitol OR IPRAGLIFLOZIN

http://www.google.com/patents/EP2105442A1

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